Novel dioximes and processes for preparing the same

ABSTRACT

NOVEL DIOXIMES OF THE FOLLOWING FORMULA:   R-C(=N-OH)-CH2-C(=N-OH)-COO-R&#39;&#39;   WHEREIN R AND R&#39;&#39; EACH REPRESENTS AN ALKYL GROUP. EXEMPLARY OF SUCH COMPOUNDS IS ETHYL 2,4-DIHYDROXYLIMINOACETYLPYROUVATE AND IS USEFUL AS AN INTERMEDIATES FOR SULFA DRUGS OR INHIBITORS FOR MONOAMINE OXIDATION ENZYME. ALKYL 2,4-DIHYDROXYLIMINOACYLPYRUVATES ARE PREPARED BY TREATING ALKYL ACYLPYRUVATES WITH HYDROXYLAMINE, THE PRODUCTS ARE ALSO PREAPRED BY TREATING ONE OF ALKYL 4HYDROXYLIMINOACYLPRUVATES OBTAINABLE BY THE PREVIOUS TREATMENT OF THE ALKYLACYLPYRUVATES WITH HYDROXYLAMINE, WITH HYDROXYLAMINE.

United States Patent 3,661,977 NOVEL DIOXIMES AND PROCESSES FOR PREPARING THE SAME Tsutomu Uchimoto, Kobe-shi, Hyogo, Japan, assignor to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed Apr. 3, 1969, Ser. No. 813,293 Claims priority, application Japan, Apr. 25, 1968, 43/27,918 Int. Cl. C07c 131/00 US. Cl. 260-482 R 9 Claims ABSTRACT OF THE DISCLOSURE Novel dioximes of the following formula:

R-C-CHzO-COOR' OH OH wherein R and R each represents an alkyl group.

Exemplary of such compounds is ethyl 2,4-dihydroxyliminoacetylpyruvate and is useful as an intermediate for sulfa drugs or inhibitors for monoamine oxidation enzyme.

Alkyl 2,4-dihydroxyliminoacylpyruvates are prepared by treating alkyl acylpyruvates with hydroxylamine. The products are also prepared by treating one of alkyl 4- hydroxyliminoacylpyruvates obtainable by the previous treatment of the alkylacylpyruvates with hydroxylamine, with hydroxylamine.

BACKGROUND OF THE INVENTION Field of the invention ncocii g-cooa' nos I 1 mom wherein R, R' and R" each represents an alkyl group, but R" coincides with an alkyl group which is brought by an alcohol, the reaction solvent.

As is illustrated by the above equations, the reaction inevitably yields two kinds of isomers, namely 3-alkyl-5- alkoxy-carbonylisooxazol [III] and 3-alkoxycarbonyl-5- alkylisooxazol [V] as end products, due to the fact that the alkyl acylpyruvates [I] are having two keto groups in one molecule and therefore two kinds [II], [IV] of monooximes are resulted therefrom.

An extraordinary resemblance in the physical and chemical behaviours of these isomers makes the separation of the both by a conventional industrial means almost impossible.

Despite the above mentioned difliculty, a separate obtaining of these isomers is considered to be extremely important. Therefore, various proposals have hitherto been made in finding a reaction condition capable of effectively promoting the formation of one isomer while suppressing that of the other to minimum. Such means have been considered to be only way of settlement.

Namely, as such a selective preparing method, it is already well known that, for example, a method which keeps the reaction condition up to the formation of the oxime [IV] acidic while rendering that of the oxime into the isooxazole [V] neutral (Japanese patent publication Showa 37/No. 17,231), and a method which keeps the reaction condition up to the formation of the oxime [II] neutral or basic and thereafter obtains the isooxazol [III] by heating the reaction mixture under an acidic condition (Japanese patent publication Showa 38/No. 22,283).

According to either one of the methods, a complete suppressing of the concomitant occurrence of the undesired isomer, has, however, not been accompilshed.

On the other hand, it has already been proposed a method which selectively produces the intended isooxazols by separating and refining the isomers which concomitantly result from the initial reaction at the step of the oximes [II] [IV] (Japanese patent publication Showa 39/No. 21,234).

SUMMARY OF THE INVENTION It is the primary object of the present invention to provide novel dioximes of the following formula:

RC-CHzC-COOR' OH OH wherein R and R each represents an alkyl group, through which dioximes either one of the above mentioned monooximes [II] [IV] can be converted to the other. Other objects of the present invention is to provide a process for preparing said dioximes. Further objects and attendant advantages thereof will be apparent to those who are conversant with the art to which the present invention pertains from the following detailed disclosure and the appended claims.

As a result of an elaborate investigation concerning the previously described reaction condition which produces the oximes and isooxazols, the present inventor has found that there is an equilibrium between the both monooximes [II] and [IV] including a novel dioxime [VI] of the present invention of an intermediate in the presence of hydroxylamine, as will be shown in the following equations, and has succeeded in the isolation of the dioxime [VI].

RC-CHzCOCOOR OH OH NOH RC-CHzC-COOR' RC-CHzC-COOR NOH NOE wherein R and R each represents an alkyl grou and a method of preparing the same which comprises; reacting alkyl acylpyruvates of the formula:

RCOCH COCOOR' wherein R and R have the same meanings as above, or alkyl 4-hydroxyliminoacylpyruvates of the formula:

RC-CHZCHZCOCOOR I iOH wherein R and R have the same meanings as above, which is obtainable by treating said alkyl acylpyruvates with hydroxylamine, with hydroxylamine.

According to the present invention and through the novel intermediate [VI] of this invention, the alkyl 4-hydroxyliminoacylpyruvates, the precursors of the 3-alkyl- -alkoxycarbonylisooxazols which have been of poor utility, can be converted into 3-alkoxycarbonyl-5-alkylisooxazols [V] which are useful as raw materials for sulfa drugs or inhibitors for monoamine oxidation enzyme, or into the alkyl 2-hydroxyliminoacylpyruvates [IV], the precursor of the isooxazol [V], and a great commercial significance can be derived therefrom.

Furthermore, the dioximes of the present invention are also useful as an intermediate for preparing 3-alkyl-5-alkoxycarbonylpyrazol having a hypoglycemic activity or antidiabetic activity.

The following examples are given for the purpose of illustration and not by way of limitation.

Example 1.-To a mixture of hydroxylamine hydrochloride (139 g., 2 mol) and 80% aqueous ethanol (500 ml.), added 158 g. (1 mol) of ethyl acetopyruvate under cooling and the combined mixture was stirred at -30 C. for 10 min.

After the addition of 50% aqueous solution of sodium hydroxide (ca. 160 g.) to neutralize the isolated hydrochloric acid and to adjust the pH value of the solution to 7, the mixture was refluxed at 80 C. for 1 hour.

The resultant mixture was then distilled under reduced pressure at a temperature below 80 C. to remove water and alcohol up to nearly dried state, and thereafter extracted with ethyl acetate.

The extract was further distilled to remove the ethyl acetate and was washed with benzene to obtain the crude dioxime.

Recrystallization of this crude substance from a mixed solution of ethyl acetate and benzene (1:4) afforded about 50 g. of refined dioxime, ethyl 2,4-dihydroxyliminoacetylpyruvate. M.P., 128.5--130 C.

Analysis.Calc. for C H N O (percent): C, 44.68; H, 6.47; N, 14.89; 0, 34.00. Found (percent): C, 44.85; H, 6.67; N, 14.58; 0, 34.16

max.

Example 2.-To a solution of hydroxylamine hydrochloride (76.4 g., 1.1 mol) in 160 ml. of water, added solution of sodium hydroxide to neutralize and to adjust the pH value of the solution to 6 while being cooled below 10 C.

After being combined with 600 ml. of an alcohol solution including 173 g. (1 mol) of ethyl 4-hydroxyliminoacetylpyruvate, the reaction mixture was kept under stirring at about 60 C. for 7 hours while being subjected to the occasional addition of a solution of sodium hydroxide to maintain the pH value Within the range from 6 to 7.

After cooling, the resultant mixture was filtered to remove the precipitated sodium chloride and distilled the alcohol off, and thereafter the mixture was poured into 1200 ml. of ethyl acetate and washed thrice with each 40 ml. of water.

Distillation of the ethyl acetate afforded 120 g. of the crude dioxime.

A similar after treatment as described in Example 1 afforded the refined dioxime, ethyl 2,4-dihydroxyliminoacetylpyruvate g., 32

What is claimed is:

1. Novel dioximes of the following formula:

RO-GHzC-OOOR' wherein R and R each represents an alkyl group of 1 to 3 carbons.

Ethyl 2,4-dihydroxyliminoacetylpyruvate. Methyl 2,4-dihydroxyliminoacetylpyruvate Ethyl 2,4-dihydroxyliminopropionylpyruvate. Methyl 2,4-dihydroxyliminopropionylpyruvate. Propyl 2,4-dihydroxyliminoacetylpyruvate. Propyl 2,4-dihydroxyliminopropionylpyruvate. A process for preparing alkyl 2,4-dihydroxyliminoacylpyruvates having a general formula RC-CHzO-COOR wherein R and R' each represents an alkyl group of 1 to 3 carbons, which comprises rearting alkyl aiylpyruvates of general formula:

RCOCH COCOOR wherein R and R have the same meaning as above, with hydroxylamine under substantially neutral conditions at a temperature at or below C. and for a time period of up to 7 hours.

9. A process as claimed in claim 8, which comprises reacting alkyl 4-hydroxyliminoacylpyruvates of the general formula:

noomoooooR' NOH wherein R and R each represents an alkyl group, with hydroxylamine.

References Cited UNITED STATES PATENTS 3,215,730 11/1965 Sp'althe et a1. 260482 OTHER REFERENCES Noller: Chem. of Organic Cornpds, p. 210.

LORRAINE A. WEINB-ERGER, Primary Examiner P. J. KILLOS, Assistant Examiner US. Cl. X.R. 

